1. Field of the Invention
The present invention relates generally to the field of thrombosis and, more specifically, to novel antithrombotic agents and methods of using the same.
2. Background Information
Cardiovascular disease is a devastating problem in the United States and worldwide. Statistics bear this out. The American Heart Association reports there were 1.5 million myocardial infarctions in the U.S. in 1991 and another 1.7 million in Europe. In 1990, in the U.S. alone, there were 779,000 hospital admissions for unstable angina, up three times as many from 1983. Angioplasty was performed on about 400,000 patients in the U.S. in 1994 and in Europe an additional 177,000 patients underwent the same treatment. In addition, approximately 500,000 U.S. patients suffer strokes each year.
Cardiovascular disease comprises four main categories: (1) coronary artery disease which leads to myocardial infarction or heart attack, (2) cerebrovascular disease causing strokes, (3) peripheral artery disease which leads to ischemia and (4) venous thrombosis, blood clots in deep veins. A common feature of these vascular diseases is thrombosis, clotting within blood vessels, which results in loss of blood flow to vital tissues and organs. The formation of a blood clot within a blood vessel, thrombosis, and the resulting loss of circulating blood can cause tissue damage and, if untreated, in many cases death.
Thrombus formation is dependent upon platelet aggregation. The interaction of blood platelets with the sub-endothelial surface of injured blood vessels and with other platelets is a major factor in the course of development of thrombi. Platelet aggregation is dependent upon the binding of fibrinogen and other serum proteins to the glycoprotein GP-IIb/IIIa complex on the platelet plasma membrane, thus cross-linking one platelet to another. GP-IIb/IIIa is a member of a large family of cell adhesion receptors known as integrins. The GP-IIb/IIIa integrin is found only on the surface of platelets and blocking it prevents platelets from aggregating and forming blood clots. Inhibition of GP-IIb/IIIa receptor binding and, therefore, of platelet aggregation is sufficient for the prevention of thrombosis.
Currently, there are various products available for preventing (aspirin, Ticlid.RTM., ReoPro.TM., dipyridamole, heparin) or dissolving blood clots (tissue-plasminogen activator (t-PA) and streptokinase). These products either destroy or remove platelets or target fibrin in an attempt to eliminate the clot. However, each has the potential serious side effect of causing prolonged bleeding. Moreover, the effects of these products are only slowly reversible.
Known GP-IIb/IIIa antagonists include antibodies which bind irreversibly to the receptor, synthetic peptides incorporating either the RGD or KGD amino acid sequences, both of which sequences are recognized by the GP-IIb/IIIa receptor, and peptide mimetics which antagonize GP-IIb/IIIa in a manner similar to the peptides. However, most, if not all, of these compounds also cause elevated bleeding.
To minimize bleeding complications, it is important to create molecules which have a higher affinity for GP-IIb/IIIa at low calcium concentrations, which is the condition at the site of clot formation, as compared to the normal, higher physiological calcium concentration found in the systemic blood supply. By inhibiting GP-IIb/IIIa at the site of a clot where calcium concentration is low, and not throughout the whole blood stream, unacceptable bleeding may be controlled when optimal doses of a drug are used. Put another way, to reduce or eliminate bleeding complications, it is important to inhibit GP-IIb/IIIa mediated platelet aggregation only at the clot site under low calcium concentration, and not in the rest of the blood stream where the calcium concentration is higher and GP-IIb/IIIa is necessary for platelet adhesion and spreading. Thus, there exists a need for GP-IIb/IIIa receptor antagonists which have a higher affinity for GP-IIb/IIIa at low calcium concentration than at physiological calcium concentration. The present invention satisfies this need and provides related advantages as well.